Salivary gland dysfunctions that accompany disease states pose a substantial health and economic burden in the US and worldwide. The debilitating consequences of radiation treatment for head and neck cancer, and of the autoimmune disorder Sjgren's Syndrome (SS), could be ameliorated with effective strategies to regenerate functional salivary epithelia and to prevent the development of fibrosis. The goal of this exploratory R21 proposal is to generate new knowledge about salivary gland repair and prevention of disease-associated fibrosis. Our preliminary studies identified a novel subpopulation of vimentin-rich cells within the SMG epithelia. These cells underwent expansion in response to injury and functioned in wound repair. They closely resembled vimentin-rich repair cell progenitors of mesodermal lineage within the lens epithelia that mediate injury repair, and whose ablation results in ineffective repair of the epithelium. Importantly, when these repair cells encounter a rigid extracellular matrix environment characteristic of injured tissues, they ca differentiate into fibrotic disease-causing myofibroblasts. Since diseases of the salivary glands result in structural defects, they are likely to trigger the repair process that involves activatio of these vinmentin-rich repair cells. In this proposal, we aim to characterize the SMG repair cells and to elucidate their role in SMG repair, including their ability to acquire myofibroblast phenotypes when the healing process is complete. Our hypothesis is that repair cell progenitors of mesodermal lineage in the SMG function as immediate responders to injury, that they mediate effective wound repair and that their fates include elimination by apoptosis and differentiation into myofibroblasts. We will test this hypothesis using genetic lineage tracing in transgenic mice that express a tamoxifen-inducible CreER under control of the endogenous vimentin promoter, coupled with ex vivo and in vivo SMG injury models. Two aims are proposed: 1) investigate the lineage of SMG repair cells, their response to injury, and the cell signaling and cytoskeletal functions essential to their reparative function; and 2) determine the fate of the repair cells following wound healing, including their ability to cause fibrotic disease Our proposed studies are significant and innovative because they will determine the identity of the SMG repair cells and explore whether these mesenchymal cells can potentially serve in salivary tissue regeneration. In addition, we will gain knowledge into how to manipulate these repair cells to prevent the development of salivary gland fibrotic disease. Our findings have the potential to be translated into effective therapeutic approaches for the regeneration of salivary gland structure and function, and to the fields of tissue injury repair and regeneration, in genera.